Extensive evidence suggests that oxidative-nitrosative/nitrative stress and inflammation are involved in most major pathological processes affecting humans, including those induced by excessive alcohol consumption. The research focus of the Laboratory of Cardiovascular Physiology and Tissue Injury (LCPTI) to understand the cellular and molecular mechanisms of the complex interplay of oxidative/nitrative stress, inflammation, lipid signaling (for example endocannabinoid signaling) and cell death pathways (e.g. poly(ADP)-ribose polymerase) in tissue injury, and to identify new therapeutic targets using clinically relevant animal models of disease (e.g., ischemia reperfusion injury, cardiomyopathies/heart failure, nephropathies, cardiovascular aging, and alcohol induced cardiovascular, liver and kidney injury and neuroinflammation). Interplay of oxidative/nitrative stress, inflammation with the endocannabinoid system (ES) in tissue injury and inflammation. Our prior studies demonstrated that cardiovascular cannabinoid 1 receptors (CB1R) contribute to the development of cardiac dysfunction and fibrosis in models of cardiomyopathies and heart failure. Excessive binge alcohol drinking may adversely affect cardiovascular function. In a recent collaborative study with Drs. Kunos and Cinar we characterized the detailed hemodynamic effects of an acute alcohol binge in mice using echocardiography, ultrasonic flow probes, pressure-volume analysis and laser speckle approach, and investigated the potential role of the endocannabinoidCB1-R signaling in these effects. We found that acute alcohol intoxication was associated with elevated levels of cardiac endocannabinoid anandamide and profound cardiovascular dysfunction and blood redistribution lasting for several hours. The adverse cardiovascular effects of acute alcohol intoxication were attenuated by CB1-R antagonist or in CB1-R knockout mice. Since there is an increasing prevalence of alcohol ingestion alone, or in combination with synthetic cannabinoid use leading to adverse cardiovascular effects in adolescents, this emerging threat raises major health concerns, and targeting CB1-R signaling may evolve as an important therapeutic option in such conditions. Our prior studies provided evidence that the activation of cannabinoid 2 receptors (CB2R) exerts anti-inflammatory effects and attenuates oxidative/nitrative stress in models of liver, cardiovascular and renal injury. However, the detection of the CB2R in cells and tissues is very problematic, because of the lack of specific antibodies. Our recent and impeding studies focus on the development of improved tools for cannabinoid 2 receptor (CB2R) detection in tissues and cell and on development of novel more selective CB2R agonists with improved selectivity and bioavailability. Our collaborative studies with Dr. Yuri Persidsky have also been exploring the role of CB2R in AIDS using humanized mouse models of the disease. Our impending studies will also focus on the understanding of the mechanisms of the activation of the endocannabinoid system during tissue injury and on the further elucidation of the role of endocannabinoid system (particularly focusing on the endocannabinoid metabolizing enzymes and CB2R in collaboration with Drs. Cravatt, Van der Stelt, Mechoulam and Kunos) in various models of liver disease, cardiomyopathy and nephropathy. Role of oxidative/nitrosative stress, inflammation, metabolic dysregulation in tissue injury Recently we have described a new clinically relevant mouse model of hepatorenal syndrome (HRS) characterized by tubular injury, tubulointerstitial nephritis and fibrosis that closely resembles the histological features seen in patients suffering from HRS. We found that in this model, disruption of renal arginine metabolism and increased oxidative/nitrative stress contributed to the collapse of renal microcirculation and tubular injury. In our future studies we will also explore the role of inflammatory mechanisms in the development of HRS. Recently it is becoming clear that there are very important interactions between various organ systems, which may promote cardiovascular disease and/or development of various severe cardiovascular complications in certain diseases (e.g. chronic liver and kidney diseases). According to recent CDC reports, chronic liver diseases are among the top contributors to mortality in the United States and in the world. These patients often develop different cardiovascular co-morbidities including heart failure, vasculopathies, renovascular hepatorenal syndrome and cardiogenic shock which ultimately largely contribute to the increased mortality observed in this patient group. Our recent and future studies have also been focused on understanding the interplay of liver and cardiovascular system in chronic liver disease. Impaired autophagy has been implicated in experimental and human pancreatitis. However, the transcriptional control governing the autophagy-lysosomal process in pancreatitis is largely unknown. In a recent collaborative study with Dr.Wen-Xing Ding we demonstrated an important role of impaired TFEB (transcription factor EB)-mediated lysosomal biogenesis in the pathogenesis of pacreatitis. Using rat models of alcohol use disorder in our collaborative studies with Drs Falk and Koob we have been exploring the effects of PCSK9 inhibition on alcohol related pathologies. Our future collaborative studies with Drs. Kunos, Koob, Gao, and Falk will also explore the role of oxidative/nitrosative stress, inflammation, lipid endocannabinoid signaling and cell death in various new rat and mouse models of alcohol use disorders.